1-47438259-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004474.4(FOXD2):​c.124C>T​(p.Arg42Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,368,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.473
Variant links:
Genes affected
FOXD2 (HGNC:3803): (forkhead box D2) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20662186).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXD2NM_004474.4 linkc.124C>T p.Arg42Cys missense_variant Exon 1 of 1 ENST00000334793.6 NP_004465.3 O60548

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXD2ENST00000334793.6 linkc.124C>T p.Arg42Cys missense_variant Exon 1 of 1 6 NM_004474.4 ENSP00000335493.6 O60548

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151664
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000136
AC:
166
AN:
1216962
Hom.:
0
Cov.:
30
AF XY:
0.000135
AC XY:
80
AN XY:
593442
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000156
Gnomad4 OTH exome
AF:
0.000202
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151664
Hom.:
0
Cov.:
32
AF XY:
0.0000405
AC XY:
3
AN XY:
74048
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 22, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.124C>T (p.R42C) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a C to T substitution at nucleotide position 124, causing the arginine (R) at amino acid position 42 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.057
T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.56
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.71
T
M_CAP
Pathogenic
0.99
D
MetaRNN
Benign
0.21
T
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Benign
0.34
N
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.25
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.053
T
Polyphen
0.0020
B
Vest4
0.13
MutPred
0.25
Loss of methylation at R42 (P = 0.0216);
MVP
0.77
ClinPred
0.48
T
GERP RS
1.5
Varity_R
0.15
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1372740408; hg19: chr1-47903931; COSMIC: COSV105895286; COSMIC: COSV105895286; API